The present invention relates to a method and apparatus for producing a sterile medical solution. More specifically, the present invention relates to a method and apparatus for producing a sterile medical solution comprising a heat sensitive component, such as glucose.
Medical solutions intended for mammals, specifically for use in humans, are required to be sterile before being infused or applied to the mammal.
One available method for sterilizing a solution is to heat the solution to a sterilizing temperature and to hold the solution at the sterilizing temperature during a sterilizing time period. To obtain a sterile medical solution intended for infusion, the solution is normally heated in an autoclave to 121xc2x0 C. for 20 minutes to thereby produce said sterile medical solution. After the sterilizing time has elapsed, the solution should be cooled to a physiologically acceptable temperature before infusion.
Known methods and apparatus for sterilizing a solution are disclosed, for example, in British Patent Applications Nos. 1,450,030; 1,504,334; and 2,034,584, and in U.S. Pat. No. 5,603,894. These prior art publications describe the preparation of a medical solution starting from tap water and producing pure water by means of a reverse osmosis device, mixing a concentrate with the pure water to produce a non-sterile medical solution, passing the non-sterile medical solution through an on-line autoclave and delivering the sterile medical solution to a recipient, such as a storage bag or a patient.
In the prior art, the complete medical solution is first prepared in a non-sterile condition and then passes through an autoclave. If the medical solution comprises heat sensitive components, these must not be exposed to too high a temperature. Normally, the temperature is increased up to the sterilizing temperature and the medical solution is maintained at the sterilizing temperature for a sterilizing time period. If the temperature is 121xc2x0 C., which is normal in an autoclave, the sterilizing time is 20 minutes to obtain a sterilizing dose, F0, of 20 minutes, as discussed below. Since the sterilizing effect is approximately exponential, an increase of the temperature by 10xc2x0 C. means a lowering of the sterilizing time by ten times. If a sterilizing temperature of 131xc2x0 C. is used, the sterilizing time should be 2 minutes, and if a sterilizing temperature of 141xc2x0 C. is used, the sterilizing time should be 12 seconds, in order to obtain a sterilizing effect, F0, of 20 minutes.
If the medical solution comprises a heat sensitive component, like glucose, that component will deteriorate during the heat treatment. An example of a medical solution containing a heat sensitive component is a dialysis fluid for peritoneal dialysis (PD). The decomposition or heat deterioration starts at a much lower temperature than the sterilizing temperature and is also present at room temperature. In order to safeguard the heat sensitive material, very short heating and cooling periods are desired so that the time/temperature profile becomes more or less rectangular. This is of greater importance if high sterilizing temperatures and short sterilization times are used.
It is known to produce sterile medical solutions by including the medical solution in a bag and placing the bag inclusive of the medical solution, in an autoclave for heating and sterilization.
A variant of this method is described in international Application No. WO 93/09820, in which the medical solution is divided into two portions, one comprising glucose at high concentration and the other comprising the rest of the solution. The double bag is heat sterilized in an autoclave. Shortly before use, the contents of the two chambers are mixed to produce the sterile medical solution. In this way, the heat sensitive component, glucose, can be autoclaved under more appropriate conditions, such as at a low pH of approximately 3.2, and at a high concentration of approximately 50%, i.e. 500 grams of glucose per liter of glucose solution.
A variant of the same methods is described in International Application No. WO 97/05852 disclosing a three-chamber-bag, in which two of the chambers comprise glucose solution and the third chamber comprises the rest of the solution. The glucose chambers may also include ionic components, such as calcium, magnesium and sodium.
A further variant is described in International Application No. WO 99/27885.
In the aforementioned concepts, the glucose portion is sterilized separately from the remaining portion of the solution. However, in order to fully sterilise the large compartment, the small glucose compartment may be over sterilized, resulting in deterioration of the heat sensitive component. A remedy for that problem is described in Swedish patent application No. 9803627-0, filed at the Swedish Patent Office on Oct. 23, 1998.
The problem of deterioration of a substance during autoclaving is also recognised in other fields of use, such as the production of sterile milk products. In order to obtain rapid heating and cooling of the product, it is not sufficient to use heat transfer by means of a heat transferring surface, like a heat exchanger. Instead, the product is mixed with steam at a predetermined temperature and pressure to condense the steam in the milk product. The milk product is sterilized by retention in a holding zone for a certain time period and at a temperature of from about 120 to 150xc2x0 C., and is then transferred to a flash cooling step, in which water is evaporated in an evaporation chamber to rapidly cool the product. Such a process is described in, for example, International Application No. WO 98/07328.
One object of the present invention is to provide a method and apparatus for producing a sterile medical solution having a gentle treatment of the heat sensitive component.
Another object of the present invention is to provide a method and apparatus in which inexpensive heaters and heat exchangers can be used.
A third object of the present invention is to provide a method and apparatus for sterilizing a medical solution in which the time/temperature profile for heating the heat sensitive component is essentially rectangular.
In accordance with the present invention, these and other objects have now been realized by the invention of a method for sterilizing a heat sensitive fluid comprising providing a first heat sensitive fluid component, providing a second fluid component, heating the second fluid component to a first temperature, the first temperature being greater than a predetermined sterilizing temperature, mixing the first heat sensitive fluid component with the heated second fluid component, whereby the first heat sensitive fluid component is heated and the heated second fluid component is cooled, and a mixed fluid is provided at a second temperature, the second temperature being at least the predetermined sterilizing temperature, and maintaining the mixed fluid at the second temperature for a predetermined sterilizing period, whereby a predetermined sterilizing dose is obtained for delivery to a recipient. Preferably, the method includes controlling the heating of the second fluid component to the first temperature to ensure that the mixed fluid reaches the second temperature.
In accordance with one embodiment of the method of the present invention, the method includes cooling the mixed fluid.
In accordance with another embodiment of the method of the present invention, the first heat sensitive fluid component comprises glucose or a glucose polymer.
In accordance with another embodiment of the method of the present invention, the second fluid component comprises water. Preferably, the second fluid component includes electrolytes, such as sodium chloride, calcium chloride, magnesium chloride, potassium chloride, sodium bicarbonate, or sodium lactate.
In accordance with another embodiment of the method of the present invention, the method includes preheating the first heat sensitive fluid component.
In accordance with another embodiment of the method of the present invention, the method includes maintaining the first heat sensitive fluid component and the second fluid component under a predetermined pressure sufficient to prevent boiling of the first heat sensitive fluid component and the second fluid component. Preferably, providing of the first heat sensitive fluid component and providing of the second fluid component comprises providing flows of these fluid components. In a preferred embodiment, the flow of the first heat sensitive fluid component comprises a first flow rate and the flow of the second fluid component comprises a second flow rate, the second flow rate being greater than the first flow rate.
In accordance with another embodiment of the method of the present invention, the method includes determining the first and second flow rates by means of a weighing device or a flow meter, and maintaining the first heat sensitive fluid component and the second fluid component at the predetermined pressure by means of a pump.
In accordance with another embodiment of the method of the present invention, the heat sensitive fluid component comprises a complex fluid comprising a plurality of first fluid components including the first heat sensitive fluid component, and the method includes sequentially sterilizing the plurality of first fluid components. In a preferred embodiment, the method includes providing a plurality of sources of concentrate fluid components for each of the plurality of first fluid components, providing a source of the second fluid component, the second fluid component comprising water, pumping one of the plurality of sources of the concentrate fluid components so as to increase the pressure thereof, pumping the water so as to increase the pressure thereof, and repeating the method for each of the plurality of first fluid components. Preferably, the method includes preheating each of the plurality of first fluid components before the mixing with the heated second fluid component. Most preferably, the preheating comprises heat exchanging each of the plurality of the first fluid components with the predetermined sterilized dose. Preferably, the preheating comprises initially heating the second fluid component by heat exchange with the predetermined sterilized dose, and further preheating the second fluid component to the first temperature by means of a separate heater, preferably comprising an electric heater. Preferably, the method includes controlling the further preheating of the second fluid component by means of a temperature sensor downstream of the maintaining of the mixed fluid at the second temperature, whereby the second temperature is maintained at the at least the predetermined sterilizing temperature.
In accordance with another embodiment of the method of the present invention, the method includes dissolving at least one powdered substance in the second fluid component to provide at least one of the first heat sensitive fluid components and the second fluid component.
In accordance with another embodiment of the method of the present invention, the method includes providing a third heat sensitive fluid component, and mixing the first heat sensitive fluid component and the third heat sensitive fluid component with the heated second fluid component. Preferably, the third heat sensitive fluid component comprises water and at least one amino acid.
In accordance with the present invention, an apparatus has also been discovered for sterilizing a heat sensitive fluid comprising a first vessel containing a first heat sensitive fluid component, a second vessel containing a second fluid component, a first heater for heating the second fluid component to a first temperature, the first temperature being greater than a predetermined sterilizing temperature, mixing means for mixing the first heat sensitive fluid component with the second fluid component to obtain a mixed fluid at a second temperature at least equal to the predetermined sterilizing temperature, and residence means for maintaining the mixed fluid at the second temperature for a predetermined sterilizing period, whereby a sterilized fluid is provided for delivery to a recipient. Preferably, the apparatus includes a controller for controlling the first heater to obtain the first temperature.
In accordance with one embodiment of the apparatus of the present invention, the apparatus includes a cooler for cooling the mixed fluid.
In accordance with another embodiment of the apparatus of the present invention, the first heat sensitive fluid component comprises glucose or a glucose polymer.
In accordance with another embodiment of the apparatus of the present invention, the second fluid component comprises water. Preferably, the second fluid component includes an electrolyte, including sodium chloride, calcium chloride, magnesium chloride, potassium chloride, sodium bicarbonate or sodium lactate.
In accordance with another embodiment of the apparatus of the present invention, the apparatus includes a preheater for preheating the first heat sensitive fluid component.
In accordance with another embodiment of the apparatus of the present invention, the apparatus includes pressurizing means for maintaining the first heat sensitive fluid component and the second fluid component at a predetermined pressure to prevent the first heat sensitive fluid component and the second fluid component from boiling.
In accordance with another embodiment of the apparatus of the present invention, the first heat sensitive fluid component and the second fluid component comprise fluid flows. Preferably, the fluid flow of the first heat sensitive fluid component has a first flow rate and the fluid flow of the second fluid component has a second flow rate, the second flow rate being greater than the first flow rate. Preferably, the apparatus includes flow rate determining means for determining the first and second flow rates, the pressurizing means comprising a pump. Preferably, the flow rate determining means comprises a weighing device or a flow meter.
In accordance with another embodiment of the apparatus of the present invention, the first heat sensitive fluid component comprises a plurality of first fluid components including the first heat sensitive fluid component, and the apparatus includes means for sequentially sterilizing each of the plurality of first fluid components and the second fluid component. In a preferred embodiment, the means for sequentially sterilizing includes supply means for supplying the plurality of first fluid components, the first vessel comprising a plurality of containers for concentrates of the plurality of first fluid components, the second vessel comprising an inlet for the second fluid component, a concentrate pump for pumping one of the plurality of first fluid components from one of the plurality of containers whereby the pressure of the one of the first fluid components is increased, a water pump for pumping the second fluid component, the second fluid component comprising water, whereby the pressure of the second fluid component is increased, the heater comprising a water heater for heating the second fluid component to the first temperature, the mixing means comprising a mixer for mixing the one of the plurality of first fluid components and the heated second fluid component to provide said mixed fluid, the residence means comprising means for maintaining the mixed fluid at the first temperature for a predetermined sterilizing period to provide a sterilized dose for delivery to a recipient, and including control means for controlling and repeating the sequential sterilizing of each of the plurality of first fluid components to provide a final sterilized complex fluid. Preferably, the apparatus includes preheating means for preheating the one of the plurality of first fluid components. Most preferably, the apparatus includes a heat exchanger for recovering heat from the sterilized dose, the heat exchanger preheating the second fluid component by heat exchange with the sterilized dose, and the apparatus including a heater for heating the second fluid component to the first temperature. Most preferably, the apparatus includes a temperature sensor downstream of the residence means for controlling the heater, whereby the first temperature comprises a temperature at least sufficient to constitute the sterilizing temperature.
In accordance with another embodiment of the apparatus of the present invention, at least one of the first and second vessels includes at least one powdered substance for dissolution in water to provide at least one of the first and second fluids.
In accordance with another embodiment of the apparatus of the present invention, the apparatus includes a third vessel for containing a third heat sensitive fluid component. Preferably, the third heat sensitive fluid component comprises water and at least one amino acid.
According to the present invention, a method of sterilizing a heat sensitive fluid is provided, comprising providing the fluid as a first heat sensitive component and a second less heat sensitive component; heating the second component to a first temperature higher than a predetermined sterilizing temperature; mixing the first component with the second component to thereby heat the first component and cool the second component, whereby the mixed components obtain a mixing temperature, which is at least equal to the sterilizing temperature; maintaining the mixed components at substantially the sterilizing temperature during a sterilization time period, so that a predetermined sterilization dose is obtained; and delivering the mixed component to a recipient.
Preferably, the first temperature is controlled to obtain a mixing temperature, which is at least equal to the sterilizing temperature. Moreover, it is preferred to cool the mixed components before delivery to the recipient.
The first heat sensitive component may comprise glucose or a glucose polymer and the second less heat sensitive component may comprise water. More specifically, the second component may include electrolytes, selected from the group of substances comprising: sodium chloride, calcium chloride, magnesium chloride, potassium chloride, sodium bicarbonate and sodium lactate.
It may be advantageous to preheat the first component. Normally, the temperature is above the boiling temperature at normal atmospheric pressure and, thus, the first and second components are maintained at a high pressure sufficient to prevent boiling.
In one embodiment, the first and second components are provided as flows of fluid, in which the flow rate of the second component is larger than the flow rate of the first component.
In order to separate the flow rate determination from the pressurising means, the flow rates are determined with a pair of scales or a flow meter, and the pressure is provided by a separate pump.
In one embodiment of the present invention, the complex fluid is divided into several fluid components, which are sterilized separately, as described above, and sequentially and then mixed with the complex fluid. This may be performed by providing sources of concentrated fluid components and pure water; pumping a first concentrated fluid from the sources of concentrated fluids, to increase the pressure thereof; pumping pure water to increase the pressure thereof, and heating the pure water to the first temperature; mixing the first concentrate and heated pure water and maintaining the mixed fluids at a sterilizing temperature for a sterilizing time to effect sterilization; delivering the sterilized and diluted concentrate fluid to a recipient; repeating the above method steps for each of the concentrated fluid components, to provide the final complex fluid for the recipient. The concentrated fluid may be preheated before being mixed with the heated water, for example by a heat exchanger by heat recovery from the sterilized fluid, which is cooled thereby.
The second fluid may be preheated by heat recovery in a heat exchanger from the sterilized fluid, which is thereby cooled, and further heated to the first temperature by a separate heating device, such as an electric heater. The heating device may be controlled by a temperature sensor positioned downstream of the maintaining step, to ensure that a sterilizing temperature is obtained.